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Medsci 314 > Lecture 7: Introduction to innate immunity > Flashcards

Lecture 7: Introduction to innate immunity Flashcards

1
Q

What do immune cells express to detect pathogens?

A

Pattern Recognition Receptors (PPRs)

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2
Q

What are PRRs designed to detect?

A

A range of Pathogen Associated Molecular Patterns (PAMPs)

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3
Q

What are some innate anatomical and physiological barriers;

A
  • intact skin
  • Ciliary clearance
  • Low stomach pH
  • Lysozyme in tears and silivia
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4
Q

What does humoral immunity mean?

A

Humoral = secreted molecules i.e not cells

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5
Q

What are some cells of the innate immune system?

A 
NK cells
Neutrophils
Mast Cells
Esinophils
Macrophages
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6
Q

What are some humoral components of the innate immune system?

A 
Complment cascade
Mannose Binding Lectin
LPS binding protein
C-reactive protein
Antimicrobial Peptides
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7
Q

What are some cells that are innate and adaptive immune responsers?

A

Natural killer T cells

Dendritric cells

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8
Q

What are cells of the adaptive immune response?

A

T cells

B Cells

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9
Q

What are the humoral components of the adaptive immune response?

A

Antibodies

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10
Q

Describe the timeline of the immune response;

A

Innate Immunity (0-4hrs)
Early induced innate response (4-96hrs)
Adaptive immune response (96hrs+)

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11
Q

Describe what happens in the innate immunity 0-4hrs:

A

Infection -> Recognition by preformed, non-specific and broadly specific effectors

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12
Q

Describe what happens in the early induced innate response (4-96hrs)

A

Infection -> Recruitment of effector cells -> Recognition of PAMPs, activation of effector cells and inflammation -> Removal of infectious agent

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13
Q

Describe what happens in the adaptive immune response (96hrs+)

A

Infection -> Transport of antigen to lymphoid organ -> Recognition by naive B and T cells -> Clonal expansion and differentiation to effector cells -> removal of infectious agent and generation of memory cells

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14
Q

How is innate immunity induced?

A

Innate immunity is induced by triggering Pattern recognition molecules (PRM) / Receptors (PRR)

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15
Q

Where are some PRR located?

A

Epthelium

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16
Q

What are the four major classes of PRM/Rs?

A

1) Soluble; c-type lectin
2) Membrane bound; Toll like Receptor

Intracellular;

3) NLRs; NOD (nucleotide binding oligomerizing Domain)-like receptor
4) RLRs; Retinoic Acid Inducible Like Receptors

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17
Q

What is example one of PRRs?

1/3

A

(mainly c type lectins)

PRR = Mannose Binding Lectin,

  • Ligand - Terminal mannose
  • Function = Activation of lectin pathway of complement
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18
Q

What is example two of PRRs? 2/3

A

PRR = c reactive protein

    • Ligand: Phosphorylcholine, bacterial and fungal membranes
  • Function; Opsonisation, activation of classical pathway of complement
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19
Q

What is example three of PRRs? 3/3

A

PRR = Lipid binding protein

Ligand = LPS

function = LPS recognition

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20
Q

What are some examples of membrane PRRs that sense extracellular pathogens?

That are involved in signalling

part 1/2

A

PRR = Toll like receptors; Multiple ligands

These once activated result in cell signalling = destroys pathogen

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21
Q

What are some examples of membrane PRRs that sense extracellular pathogens?

That are involved in internalisation?

part 2/2

A

PRR = Macrophage mannose receptor
- Ligand = terminal mannose

PRR = Macrophage scavenging receptor
- Ligand = LPS, multiple ligands

PRR = MARCO
- Ligand: bacterial cell walls

These result in phagocytosis

22
Q

What are some examples of intracellular PRRs?

A

NOD
NLRPS
RLR
DNA sensors

They all have mutliple domains and multiple ligands

23
Q

What is the function of intracellular PRRs?

A

Activation of NFkB and MAP kinases, type-1 IFN and Caspase 3 activation, IL-1B

Apoptosis in virally infected cells

24
Q

What are some general features of PAMPs?

A
  • essential for survival
  • Conserved
  • Common to entire classes of microbes
  • Complex/unique 3D molecular structure
  • Typically carbohydrates, lipids (not proteins)
  • Often have repetitive structures

These do not reflect self molecules often

25
Q

What are some examples of DAMPS?

A
  • High mobility box 1 (nuclear protein)
  • Calgranulin A, B (intracellular)
  • Serum Amyloid A (acute phase protein)
26
Q

What are some receptors of DAMPs?

A

RAGE
TLR2/4
TREM

Receptors recognise endogenous materials in locations they shouldnt be.

27
Q

What can DAMPS signal for?

A

Cell stress, Necrosis

28
Q

What some examples of common PAMPs?

A

TLR2 is expressed in viruses, gram +ve and -ve bacteria, fungi and protozoa i.e widely expressed.

TLR9 is also common

RLRs less common - viruses
NLRs - bacteria and fungi

29
Q

What do TLR receptors often form?

A

Most TLRs form homodimers to recognise cell materials

Except TLR2 will form heterodimers to recognise cell materials

30
Q

What is special about TLR4?

A

TLR4 recognises LPS, but needs help from associated molecules.

31
Q

Describe TLR expression:

A

TLR is not expressed evenly across cell types.

32
Q

What are the three signals for an effective memory response?

A

Danger -> Antigen -> co-stimulation

33
Q

Describe and effective memory response;

A 
Immature DC (expresses PRR and TLR)
- Pathogen is binds to PRR -> This causes MHC expression (of peptide fragment) which binds TcR which generates a memory response
  • Pathogen or soluble PAMP also binds TLR -> results in release of IL2 which attracts t cells / is danger signal. TLR also causes CD80/86 expression on the DC. CD28 on T cell binds this.
34
Q

How important is the TLR family?

A

Knockout mice with TLR4 mutation became very susceptible to gram negative infections

35
Q

Where are TLRs located in cells?

A

On the cell surface and intracellularly on the endosomal surface

36
Q

What are the key molecules of the innate immune system?

A

PRM
PRR
PAMPs
DAMPs

37
Q

What is the signalling pathway of the TLR family?

A

They can signal danger by causing the cell to release ILs. They also can cause the up regulation of CD receptors

38
Q

What is a key feature of TLRs?

A

They are highly specific

39
Q

Whats an example of TLR1/2 receptor recognition and signalling;

A

TLR1 and TLR2 both bind PAM3-CSK4 dimerising these molecules and bringing their cytoplasmic TIR domains into close proximity

i.e TLR can dimerise heterogenously to bind PAMPs

40
Q

Describe TLR 4 PAMP recognition example;

A
  • Recognition of LPS by TLR4 is both direct and indirect (via MD2)
  • MD2 is a critical accessory protein
  • Two additional accessory proteins are involved; Lipid binding protein binds CD14 and transfers to MD2
41
Q

What can the the consequence of TLR activation?

A

Consequences of TLR signalling;

  • Activation of adaptive proteins
  • leading to a signalling ubiquination cascade
  • that can lead to IKB being phosphorylated, no longer inhibiting NKkB
  • leading to the production of proinflammatory cytokines
42
Q

Why is TLR activation of proinflammatory cyotkines bad?

A

Pro-inflammatory cytokines contribute to inflammation by;

  • Amplification of response: simulates migration of additional effector molecules and cells from blood to local site
  • Local barrier to prevent spread of infection: induces local blood clotting
  • Promotion of tissue repair
43
Q

What can systemic production of cytokines result in?

A

Systemic

  • IL-1b can lead to fever, IL6 prodcution
  • Mobilisation of metabolites, fever, shock (TNFa)
  • Acute phase protein production (IL6), fever
44
Q

What is TNFa key for?

A

Transmitting stress signal

45
Q

Write some notes on TNFa;

A
  • Activated through NF-kB pathway
  • Two receptors ; TNF-RI, TNF-RII
  • TNF-R1 has death domain which recruits TRADD
46
Q

What are the first four positive effects of TNF-a? 4/9

A
  • Increases phagocytosis
  • Raises body temperature
  • Induces acute-phase response proteins from liver
  • Induces inflammatory response mechanisms and vascular responses
47
Q

What are the 4-9/9 positive effects of TNF-a?

A
  • Stimulates migration of DC and migration to lymph nodes
  • Increases lymphocytes migration to site
  • Increases platelet adhesion to blood vessels
  • Containment of infection to the local site
  • Pain and tenderness
48
Q

What are four negative effects of TNFa?

A
  • Oedema
  • Neutropenia (loss of neutrophils from blood)
  • Change in blood volume through its effects on the CNS
  • Vascular leakage and hypotension
49
Q

What are five more effects of TNFa?

A
  • Elevated temperatures
  • Organ failure
  • Muscle wasting
  • Septic shock
  • Death
50
Q

What regulates the danger signal?

A

Innate receptors

51
Q

What recognises LPS?

A

TLR4

52
Q

What is the central element in TLR signalling?

A

NF-kB

Medsci 314 (31 decks)

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